The Myc family of transcriptional regulators consists of highly conserved, basic helix loop helix (bHLH) containing proteins that regulate cell proliferation, differentiation and apoptosis presumably by activation or repression of the transcription of different sets of target genes. The Myc proteins contain three major domains: 1) the N-terminal domain, which consists of the transactivation and repression domains as well as the two highly conserved (90%) myc box regions (myc box I and myc box II) that are vital for all Myc functions; 2) the central region; and 3) the C-terminal domain that contains the bHLH/leucine rich region required for both DNA binding and dimerization with the bHLH protein Max. Once dimerized with Max, the Myc proteins can bind to the E-box sequence, CACGTG, present in the promoters of target genes and activate transcription. Alternatively, Myc can repress transcription by binding to initiator elements (consensus YYCAYYYYY; Y=pyrimidine) or GC rich regions (e.g., gadd45) in target genes. In addition to Max, Myc proteins interact with a variety of other proteins that facilitate or inhibit various cellular functions, including TRRAP (transactivation through chromatin remodeling, and TFII-1, SP-1 or Miz-1 (repression). Conversely, c-Myc functions are inhibited by interactions with Rb-related p107, Bin1, BRCA1 and p19ARF. Together, these various interactions enable Myc proteins to perform their designated functions in a precise and controlled manner. However, deregulated expression of Myc family members, such as that which results from gene amplification or translocation are found in many cancers.
Recent advances in small molecule drug design and synthesis have resulted in extensive research into molecular-targeted therapy for cancer and the isolation of various small molecules that regulate particular cell functions (e.g., cell cycle, apoptosis, angiogenesis). Such an approach has the potential to be more effective and less toxic than current treatment regimens. Myc function in cells is mediated by a series of interactions between Myc family members and other cellular proteins. Thus, small molecules that are able to interfere with one or more of these interactions have the potential to be developed into anti-Myc drugs. While much of the information on protein-protein interactions has been obtained through functional studies with c-Myc, N-myc is able to substitute for c-Myc under various conditions and should, therefore, be expected to share many of the same interactions. Thus, molecules that are identified in a small molecule screen for one Myc family member would be expected to identify compounds that are active against the other family members. Since Myc proteins function as transcriptional regulators, the use of a reporter (e.g., luciferase) specific for Myc-mediated transcription can be used to detect alterations in Myc activity within cells in the presence of novel small molecules.
N-myc gene amplification is one of the most powerful prognostic indicators for neuroblastoma, the most common solid tumor of young children, and is associated with rapid tumor progression, advanced stage disease and poor outcome. Overexpression of the c-Myc gene is among is among the most frequent events in human cancer and is often associated with more aggressive, poorly differentiated and metastatic types of tumors including those arising in colon, breast, prostate, ovary and skin. Thus, abrogation of Myc function in this class of tumors should have therapeutic benefit without significant side effects of normal tissues that are not dependent on high levels of Myc for survival.
Thus, there exists a need in the art for methods to treat cancer by inhibiting the activity of the c-Myc oncoprotein.